The renal mitochondrial toxicity of cephalosporins: specificity of the effect on anionic substrate uptake.
Previous work in this laboratory has demonstrated a reduction by the nephrotoxic beta-lactam antibiotics cephaloridine, cephaloglycin and imipenem of renal mitochondrial uptake of and respiration with the anionic substrate succinate. The present studies were done to test further the hypothesis that reduced substrate uptake and decreased respiration are causally related. Using cephaloridine in the rabbit, we examined the specificity of this association in regard to the toxic cephalosporin insult, the involvement of renal mitochondria and the reduction of carrier-mediated anionic substrate transport. 1) Specificity of insult in renal cortical mitochondria: cephaloridine (300 mg/kg bwt. i.v., 1 hr before sacrifice) reduces both the uptake of and respiration with succinate, whereas the same dose of cephalexin, which is not nephrotoxic, has neither effect; 25 min of acute unilateral renal artery occlusion reduces both the uptake of and respiration with succinate, but, unlike cephaloridine, ischemia causes a large increase of substrate efflux; and the respiratory toxins cyanide (1 mM) and oligomycin (2 micrograms/g of protein) reduce respiration by a direct effect on the mitochondrial respiratory chain and therefore have no effect on substrate uptake. 2) Specificity of target organ: cephaloridine has no significant effect on either the uptake of or respiration with succinate in hepatic mitochondria.(ABSTRACT TRUNCATED AT 250 WORDS)
Tune
B M
BM
Department of Pediatrics, Stanford University School of Medicine, California.
Hsu
C Y
CY
D000244:Adenosine Diphosphate / Q000378:metabolism; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002506:Cephalexin / Q000494:pharmacology; D002509:Cephaloridine / Q000494:pharmacology; D002511:Cephalosporins / Q000633:toxicity*; D005260:Female; D066298:In Vitro Techniques; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects; D010710:Phosphates / Q000378:metabolism; D011773:Pyruvates / Q000494:pharmacology; D019289:Pyruvic Acid; D011817:Rabbits
D002511:Cephalosporins; D010710:Phosphates; D011773:Pyruvates; D000244:Adenosine Diphosphate; D019289:Pyruvic Acid; D002509:Cephaloridine; D002506:Cephalexin